ENTYCE- capromorelin tartrate solution

ENTYCE by

Drug Labeling and Warnings

ENTYCE by is a Animal medication manufactured, distributed, or labeled by Aratana Therapeutics, Inc., Elanco US Inc., Halo Pharmaceuticals, Cambrex Charles City. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

SPL UNCLASSIFIED SECTION

For oral use in dogs only Appetite Stimulant Caution:

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Description:

ENTYCE® (capromorelin oral solution) is a selective ghrelin receptor agonist that binds to receptors and affects signaling in the hypothalamus to cause appetite stimulation and binds to the growth hormone secretagogue receptor in the pituitary gland to increase growth hormone secretion. The empirical formula is C28H35N5O4·C4H6O6 and the molecular weight 655.70. The chemical name is 2-amino-N-[2-(3aR-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yI)- 1R-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartrate.

The chemical structure of capromorelin tartrate is:

Indication:

ENTYCE (capromorelin oral solution) is indicated for appetite stimulation in dogs.

Dosage and Administration:

Administer ENTYCE orally at a dose of 3 mg/kg (1.4 mg/lb) body weight once daily.

To administer ENTYCE, gently shake the bottle, and then withdraw the appropriate amount of solution using the provided syringe. Rinse syringe between treatment doses.

The effectiveness of ENTYCE has not been evaluated beyond 4 days of treatment in the clinical field study (See Effectiveness).

Contraindications:

ENTYCE should not be used in dogs that have a hypersensitivity to capromorelin.

Warnings:

Not for use in humans. Keep this and all medications out of reach of children and pets. Consult a physician in case of accidental ingestion by humans. For use in dogs only

Precautions:

Use with caution in dogs with hepatic dysfunction. ENTYCE is metabolized by CYP3A4 and CYP3A5 enzymes (See Clinical Pharmacology).

Use with caution in dogs with renal insufficiency. ENTYCE is excreted approximately 37% in urine and 62% in feces (See Adverse Reactions and Clinical Pharmacology).

The safe use of ENTYCE has not been evaluated in dogs used for breeding or pregnant or lactating bitches.

Adverse Reactions:

In a controlled field study, 244 dogs were evaluated for safety when administered either ENTYCE or a vehicle control (solution minus capromorelin) at a dose of 3 mg/kg once daily for 4 days. Enrolled dogs had a reduced or absent appetite for a minimum of 2 days prior to day 0 and had various medical conditions: arthritis (40); gastrointestinal disease (24); allergy (22); dental disease (22); cardiovascular disease (16); renal disease (13); and others. Some dogs may have experienced more than one of the adverse reactions during the study. The following adverse reactions were observed:

Table 1: Adverse Reactions reported in dogs administered ENTYCE oral solution compared to vehicle control

Adverse Reactions	ENTYCE (n = 171) n (%)	Vehicle Control (n = 73) n (%)
GASTROINTESTINAL
Diarrhea	12 (7.0 %)	5 (6.8 %)
Vomiting	11 (6.4 %)	4 (5.5 %)
Hypersalivation	4 (2.3 %)	0 (0.0 %)
Abdominal discomfort	2 (1.2 %)	0 (0.0 %)
Flatulence	2 (1.2%)	0 (0.0 %)
Nausea	2 (1.2%)	0 (0.0 %)
CLINICAL PATHOLOGY
Elevated blood urea nitrogen	7 (4.1 %)	2 (2.7 %)
Elevated phosphorus	4 (2.3 %)	1 (1.4%)
Elevated creatinine	1 (0.6 %)	1 (1.4 %)
OTHER
Polydipsia	7 (4.1 %)	1 (1.4 %)
Lethargy/depression	2 (1.2%)	0 (0.0 %)

The following adverse reactions were reported in < 1% of dogs administered ENTYCE: hyperactivity, increase fecal volume, increase gut sounds, and polyuria.

To report suspected adverse drug events and/or to obtain a copy of the Safety Data Sheet (SDS) or for technical assistance, call Aratana Therapeutics at 1-844-272-8262.

For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or at http://www.fda.gov/AnimalVeterinary/SafetyHealth

(continued on other side)

Clinical Pharmacology:

Following oral administration of ENTYCE at a dose of 3 mg/kg to 12 Beagle dogs, absorption of capromorelin was rapid with the maximum concentration (Cmax) reached within 0.83 hr (Tmax). After Cmax, the plasma concentrations declined mono-exponentially with a short terminal half-life (T½) of approximately 1.19 hrs. There were no gender differences in capromorelin pharmacokinetics. The exposure (Cmax and AUC) of capromorelin increased with dose, but the increases were not dose proportional following single and repeat once daily administrations of capromorelin. There was no drug accumulation following repeat oral administration.

Table 2. Plasma PK parameters following oral administration of 3 mg/kg of ENTYCE

Parameter	Mean	SD
Tmax(hr)	0.83	0.58
cmax(ng/mL)	330	143
AUCt (ng*hr/mL)	655	276
AUCinf (ng*hr/mL)	695	262
T½ (hr)	1.19	0.17

The mean absolute oral bioavailability of capromorelin was 44%. The mean total plasma clearance and volume of distribution was 18.9 mL/min/kg and 2.0 L/kg, respectively. Capromorelin was not highly bound (unbound fraction 51%) to plasma protein. The protein binding was concentration-independent over the range of 10 to 1000 ng/mL. In vitro (human liver microsomes) and in vivo (rats) metabolism studies suggest that capromorelin is metabolized by hepatic enzymes, mainly CYP3A4 and CYP3A5. Therefore, drugs that inhibit CYP3A4 and CYP3A5 activity may affect capromorelin metabolism. Following oral administration of radio-labelled capromorelin to dogs, capromorelin was excreted in urine (37%) and in feces (62%) within 72 hours.

Effectiveness:

Laboratory Effectiveness Study: Twenty four healthy Beagle dogs (6 dogs per sex in each group) with normal appetite were randomized into two groups and dosed daily with ENTYCE (capromorelin oral solution) at 3 mg/kg/day or vehicle control (solution minus capromorelin) to compare food intake over a 4-day period. The dogs were 13 months of age and weighed between 6.5 and 12.5 kg at the time of randomization. Six dogs administered ENTYCE repeatedly exhibited salivation post dosing and two dogs administered vehicle control exhibited salivation only one time on study day 0. Emesis was observed in one dog administered ENTYCE on study day 1. Dogs administered ENTYCE at a dose of 3 mg/kg/day for 4 consecutive days had statistically significantly increased food consumption compared to the vehicle control group (p< 0.001).

Clinical Field Study: Effectiveness was evaluated in 177 dogs (121 dogs in the ENTYCE group and 56 dogs in the vehicle control group) in a double-masked, vehicle controlled field study. Dogs with a reduced appetite or no appetite, with various medical conditions, for a minimum of 2 days prior to day 0 were enrolled in the study. The dogs ranged in age from 4 months to 18 years. Dogs were randomized to treatment group and dosed once daily for 4 days with ENTYCE at 3 mg/kg or vehicle control. Dogs were assessed for appetite by owners on day 0 and day 3 ± 1 using an "increased", "no change" or "decreased" scoring system. Dogs were classified as a treatment success if the owner scored their dog's appetite as "increased" on day 3 ± 1. The success rates of the two groups were significantly different (p = 0.0078); 68.6% (n = 83) of dogs administered ENTYCE were successes, compared to 44.6% (n = 25) of the dogs in the vehicle control group.

Animal Safety:

In a 12-month laboratory safety study, 32 healthy Beagle dogs (4 dogs per sex per group) approximately 11-12 months of age and weighing 9-13.6 kg were dosed orally with capromorelin in deionized water daily at 0X (placebo), 0.3 (0.13X), 7 (3.07X), and 40 (17.5X) mg/kg/day. Administration of capromorelin was associated with increased salivation and reddening/swollen paws, increased liver weights and hepatocellular cytoplasmic vacuolation. Treatment related decreases were seen in red blood cell count, hemoglobin and hematocrit in the 40 mg/kg group. Pale skin, pale gums, and decreased red blood cell count, hemoglobin and hematocrit were observed in one dog administered 40 mg/kg/day. Increases were seen in cholesterol, high density lipoproteins, and the liver specific isozyme of serum alkaline phosphatase in the 40 mg/kg group. Growth hormone and insulin-like growth factor 1 plasma levels were increased in all groups administered capromorelin. There were no effects noted on gross necropsy. Capromorelin levels were similar in plasma collected on days 90, 181, and 349 indicating no accumulation of drug.

Storage Conditions:

Store at or below 86° F (30° C)

How Supplied:

30 mg/mL flavored solution in 10 mL, 15 mL and 30 mL bottles with measuring syringe NADA 141-457, Approved by FDA

US Patent: 6,107,306 US Patent: 6,673,929 Made in Canada

ARATANA
Therapeutics®

Manufactured for:
Aratana Therapeutics, Inc.
Leawood, KS 66211

ENTYCE is a trademark of Aratana Therapeutics, Inc. © Aratana Therapeutics, Inc.

C-A213

June 2016

Principal Display Panel - Entyce 10 mL Carton Label

NDC: 86026-021-03

entyce®

(capromorelin oral solution)

30 mg/mL

For oral use in dogs only

Appetite Stimulant

Caution: Federal (USA) law restricts
this drug to use by or on the order
of a licensed veterinarian.

10 mL Flavored Solution

NADA 141-457

Approved by FDA

ARATANA
THEARAPEUTICS

Principal Display Panel - Entyce 10 mL Label

entyce®

(capromorelin oral solution)

30 mg/mL

For oral use in dogs only

Caution: Federal (USA) law restricts this drug to
use by or on the order of a licensed veterinarian.

10 mL Flavored Solution

NADA 141-457

Approved by FDA

ARATANA
THEARAPEUTICS

Principal Display Panel - Entyce 15 mL Carton Label

NDC: 86026-021-04

entyce®

(capromorelin oral solution)

30 mg/mL

For oral use in dogs only

Appetite Stimulant

Caution: Federal (USA) law restricts
this drug to use by or on the order
of a licensed veterinarian.

15 mL Flavored Solution

NADA 141-457

Approved by FDA

ARATANA
THEARAPEUTICS

Principal Display Panel - Entyce 15 mL Label

entyce®

(capromorelin oral solution)

30 mg/mL

For oral use in dogs only

Caution: Federal (USA) law restricts this drug to use by or on the
order of a licensed veterinarian.

15 mL Flavored Solution

NADA 141-457

Approved by FDA

ARATANA
THEARAPEUTICS

Principal Display Panel - Entyce 30 mL Carton Label

NDC: 86026-021-06

entyce®

(capromorelin oral solution)

30 mg/mL

For oral use in dogs only

Appetite Stimulant

Caution: Federal (USA) law restricts
this drug to use by or on the order
of a licensed veterinarian.

30 mL Flavored Solution

NADA 141-457

Approved by FDA

ARATANA
THEARAPEUTICS

Principal Display Panel - Entyce 30 mL Label

entyce®

(capromorelin oral solution)

30 mg/mL

For oral use in dogs only

Caution: Federal (USA) law restricts
this drug to use by or on the order
of a licensed veterinarian.

30 mL Flavored Solution

NADA 141-457

Approved by FDA

ARATANA
THEARAPEUTICS

INGREDIENTS AND APPEARANCE

ENTYCE 
capromorelin tartrate solution

Product Information
Product Type	PRESCRIPTION ANIMAL DRUG	Item Code (Source)	NDC: 86026-021
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
capromorelin tartrate (UNII: 4150VMF5EP) (capromorelin - UNII:0MQ44VUN84)	capromorelin tartrate	30 mg  in 1 mL

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 86026-021-03	1 in 1 CARTON
1		10 mL in 1 BOTTLE, PLASTIC
2	NDC: 86026-021-06	1 in 1 CARTON
2		30 mL in 1 BOTTLE, PLASTIC
3	NDC: 86026-021-04	1 in 1 CARTON
3		15 mL in 1 BOTTLE, PLASTIC

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141457	02/08/2017

Labeler - Aratana Therapeutics, Inc. (063350207)

Registrant - Elanco US Inc. (966985624)